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Administration of AdVEGF-All6A+ to Myocardium of Individuals With Diffuse CAD Via Minimally Invasive Surgery

Primary Purpose

Coronary Artery Disease

Status

Withdrawn

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

AdVEGF-All6A+

AdNull

About this trial

This is an interventional treatment trial for Coronary Artery Disease focused on measuring Diffuse Coronary Artery Disease (CAD)

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Males and females, age 18 to 90
Demonstrable reversible left ventricular ischemia in viable myocardium as assessed by ST segment/T wave abnormalities detected by exercise testing with 99mTc-sestamibi single-photon emission computed tomography (SPECT) prior to and following the exercise test
Individuals who have coronary artery disease (CAD) but have angina refractory to medical therapy
Individuals who experience angina class II-IV as defined by the Canadian Cardiovascular Society
Individuals who have had a coronary angiogram in the prior 6 months demonstrating diffuse coronary artery disease and are not considered to be eligible for coronary artery bypass surgery, stents, or angioplasty, because of the lack of suitable target lesions
Individuals must be medically capable of undergoing open thoracotomy
Individuals must have neutralizing anti-adenovirus serotype 5 titer ≤160; this criteria is based on the knowledge that some individuals have high anti Ad5 neutralizing antibody titer which may limit efficacy
Hematocrit >30%
WBC <10,000
Normal prothrombin, partial thromboplastin time (excluding IV heparin therapy)
Normal liver-related serum parameters
Glomerular filtration rate (GFR) > 30 ml/min
No evidence of active infection of any types, including adenovirus, hepatitis virus (A, B or C) or human immunodeficiency virus
No evidence of central nervous system, major psychiatric, musculoskeletal or immune disorder
No allergy to the vehicle used to suspend the virus or contrast materials used in radiographic procedures
Fertile or infertile individuals; it will be recommended that fertile individuals utilize barrier birth control measures to prevent pregnancy during and for 2 months following the administration of the vector
Individuals not receiving experimental medications or participating in another experimental protocol for at least 4 weeks prior to entry to the study.
Individuals must be able to exercise for at least 90 seconds but no more than 15 min on a modified Bruce protocol exercise treadmill test while exhibiting angina with concurrent 1 mm horizontal or downsloping ST-segment depression
The study individual must be able to undergo the procedures in the protocol
Willingness to participate in the study
Capable of providing informed consent

Exclusion Criteria:

Individuals who do not meet the inclusion criteria will be unable to participate in the protocol
Individuals in whom participation in the study would compromise the normal care and expected progression of their disease
Individuals receiving corticosteroids or other immunosuppressive medications
Individuals with uncontrolled diabetes
Diabetic individuals with significantly abnormal ophthalmologic exam (moderate or greater disease severity)
Individuals with hypercholesterolemia (LDL above 190 mg/dl or total cholesterol above 240 mg/dl)
Body mass index >35
Recent (<6 wk) cerebral vascular accident
Recent (<6 wk) transmural myocardial infarction
Evidence of infection defined by elevated white blood cell (WBC) count, temperature >38.5ºC, infiltrate on chest x-ray
Unable to undergo cardiac MRI with gadolinium contrast
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values 2.5 greater than normal limits
Prior cardiac transplantation
Electrocardiograph abnormalities that would interfere with ST-segment analysis
Untreated malignant ventricular arrhythmia
Valvular heart disease requiring surgical intervention
Preoperative congestive heart failure (New York Heart Association Function Class III or IV or ejection fraction (EF) <25%
Uncontrollable asthma or chronic obstructive pulmonary disease (COPD)
Greater than first degree heart block or sinus node dysfunction without a functional pacemaker
Systolic blood pressure less than 90 mmHg
Known hypersensitivity to adenosine
Pregnancy or currently lactating
Prior participation in cardiac gene and/or cardiac cell therapy

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Part A, Group 1 - 10^8 pu

Part A, Group 2 - 10^9 pu

Part A, Group 3 - 10^10 pu

Part B, Group 1 - AdVEGF-All6A+

Part B, Group 2 - AdNull placebo

Arm Description

Part A is a dose-escalation, open-label study, administering 3 doses of AdVEGF-All6A+ to n=9 individuals, with n=3 each at 10^8, 10^9, and 10^10 particle units. The purpose of Part A is to determine the highest tolerable dose. Group 1 will receive 10^8 particle units.

Part B (n=32 subjects) is a randomized, double blind, placebo-controlled study that will compare the AdVEGF-All6A+ vector (n=24) to a placebo, AdNull (n=8). Group 1 will receive AdVEGF-All6A+ at the highest tolerable dose determined in Part A.

Part B (n=32 subjects) is a randomized, double blind, placebo-controlled study that will compare the AdVEGF-All6A+ vector (n=24) to a placebo, AdNull (n=8). Group 2 will receive AdNull, the placebo vector.

Outcomes

Primary Outcome Measures

Time to 1 mm ST depression during exercise-stress testing

Collect the times during the stress-test

Secondary Outcome Measures

Exercise-stress echocardiogram

To assess segmental wall motion in treated territories

Angina

measured by the Canadian Cardiovascular Society Functional Classification of Angina Pectoris

Cardiac MRI +/- adenosine stress

To assess segmental wall motion and perfusion in treated territories

Full Information

NCT ID

NCT01757223

First Posted

October 10, 2012

Last Updated

January 24, 2021

Sponsor

Weill Medical College of Cornell University

1. Study Identification

Unique Protocol Identification Number

NCT01757223

Brief Title

Administration of AdVEGF-All6A+ to Myocardium of Individuals With Diffuse CAD Via Minimally Invasive Surgery

Official Title

Phase I/II Study, Administration of AdVEGF-All6A+, a Replication Deficient Adenovirus Vector Expressing a cDNA/Genomic Hybrid of Human Vascular Endothelial Growth Factor to the Ischemic Myocardium...

Study Type

Interventional

2. Study Status

Record Verification Date

January 2021

Overall Recruitment Status

Withdrawn

Why Stopped

Closure due to lack of funding.

Study Start Date

December 2020 (Anticipated)

Primary Completion Date

October 2030 (Anticipated)

Study Completion Date

October 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Weill Medical College of Cornell University

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The proposed Phase I/II clinical trial will be used to determine the safety and toxicity of direct administration of the vector AdVEGF-All6A+ to the ischemic myocardium and to generate preliminary evidence regarding whether direct administration of AdVEGF-All6A+ to the ischemic myocardium will induce growth of collateral blood vessels and improve cardiac function. This is a three-part, multinational/multi-center, placebo controlled study.

Detailed Description

Coronary artery disease (CAD) is the predominant cause of heart failure, a major cause of death and disability throughout the world. Although prognosis of patients with CAD has been greatly improved by advances in cardiovascular treatment, it is still the first cause of death in the USA. Treatment options for CAD include diet, exercise, medication, balloon angioplasty with or without stenting, atherectomy and bypass surgery. For many patients, however, the disease is diffuse and stenting or bypass surgery is not an option. A new strategy to treat these patients is to use gene therapy to induce new networks of new blood vessels to bypass the arterial system that is blocked, thus providing circulation to deliver oxygen needed by the tissue. By administering a gene coding for vascular endothelial growth factor (VEGF) to the myocardium, new networks of blood vessels can be created using the genetic material for VEGF. In experimental animal studies, VEGF is effective at treating ischemia of organs and is safe. The most direct method of transferring genes to myocardium is by injection under direct vision during a minimally invasive thoracic surgery. For the present study, the VEGF gene will be delivered to the myocardium using a modified adenovirus (Ad) as a carrier. The study is designed to test the safety and efficacy of AdVEGF-All6A+.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Coronary Artery Disease

Keywords

Diffuse Coronary Artery Disease (CAD)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part A, Group 1 - 10^8 pu

Arm Type

Experimental

Arm Description

Arm Title

Part A, Group 2 - 10^9 pu

Arm Type

Experimental

Arm Description

Arm Title

Part A, Group 3 - 10^10 pu

Arm Type

Experimental

Arm Description

Arm Title

Part B, Group 1 - AdVEGF-All6A+

Arm Type

Experimental

Arm Description

Arm Title

Part B, Group 2 - AdNull placebo

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

AdVEGF-All6A+

Intervention Description

We will administer AdVEGF-All6A+, an adenovirus vector carrying the genetic material for human vascular endothelial growth factor to the ischemic myocardium of individuals with diffuse coronary artery disease.

Intervention Type

Biological

Intervention Name(s)

AdNull

Intervention Description

AdNull is an adenovirus vector identical to AdVEGF-All6A+, except that it does not encode for a transgene.

Primary Outcome Measure Information:

Title

Time to 1 mm ST depression during exercise-stress testing

Description

Collect the times during the stress-test

Time Frame

3 mos (Part A); 6 mos (Part B)

Secondary Outcome Measure Information:

Title

Exercise-stress echocardiogram

Description

To assess segmental wall motion in treated territories

Time Frame

Twice before vector administration at -30 days and -15 days (± 5 days), and will be repeated at day 90 post-vector for Part A and day 90 and 180 post-vector for Part B

Title

Angina

Description

measured by the Canadian Cardiovascular Society Functional Classification of Angina Pectoris

Time Frame

Twice pre-vector administration at -30 days and -15 days, and repeated at 30 and 90 days post-vector for Part A and at 30, 90 and 180 days post-vector for Part B

Title

Cardiac MRI +/- adenosine stress

Description

To assess segmental wall motion and perfusion in treated territories

Time Frame

Once pre-vector and repeated at 90 days post vector for Part A, and 180 days post-vector for Part B

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

90 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Males and females, age 18 to 90 Demonstrable reversible left ventricular ischemia in viable myocardium as assessed by ST segment/T wave abnormalities detected by exercise testing with 99mTc-sestamibi single-photon emission computed tomography (SPECT) prior to and following the exercise test Individuals who have coronary artery disease (CAD) but have angina refractory to medical therapy Individuals who experience angina class II-IV as defined by the Canadian Cardiovascular Society Individuals who have had a coronary angiogram in the prior 6 months demonstrating diffuse coronary artery disease and are not considered to be eligible for coronary artery bypass surgery, stents, or angioplasty, because of the lack of suitable target lesions Individuals must be medically capable of undergoing open thoracotomy Individuals must have neutralizing anti-adenovirus serotype 5 titer ≤160; this criteria is based on the knowledge that some individuals have high anti Ad5 neutralizing antibody titer which may limit efficacy Hematocrit >30% WBC <10,000 Normal prothrombin, partial thromboplastin time (excluding IV heparin therapy) Normal liver-related serum parameters Glomerular filtration rate (GFR) > 30 ml/min No evidence of active infection of any types, including adenovirus, hepatitis virus (A, B or C) or human immunodeficiency virus No evidence of central nervous system, major psychiatric, musculoskeletal or immune disorder No allergy to the vehicle used to suspend the virus or contrast materials used in radiographic procedures Fertile or infertile individuals; it will be recommended that fertile individuals utilize barrier birth control measures to prevent pregnancy during and for 2 months following the administration of the vector Individuals not receiving experimental medications or participating in another experimental protocol for at least 4 weeks prior to entry to the study. Individuals must be able to exercise for at least 90 seconds but no more than 15 min on a modified Bruce protocol exercise treadmill test while exhibiting angina with concurrent 1 mm horizontal or downsloping ST-segment depression The study individual must be able to undergo the procedures in the protocol Willingness to participate in the study Capable of providing informed consent Exclusion Criteria: Individuals who do not meet the inclusion criteria will be unable to participate in the protocol Individuals in whom participation in the study would compromise the normal care and expected progression of their disease Individuals receiving corticosteroids or other immunosuppressive medications Individuals with uncontrolled diabetes Diabetic individuals with significantly abnormal ophthalmologic exam (moderate or greater disease severity) Individuals with hypercholesterolemia (LDL above 190 mg/dl or total cholesterol above 240 mg/dl) Body mass index >35 Recent (<6 wk) cerebral vascular accident Recent (<6 wk) transmural myocardial infarction Evidence of infection defined by elevated white blood cell (WBC) count, temperature >38.5ºC, infiltrate on chest x-ray Unable to undergo cardiac MRI with gadolinium contrast Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values 2.5 greater than normal limits Prior cardiac transplantation Electrocardiograph abnormalities that would interfere with ST-segment analysis Untreated malignant ventricular arrhythmia Valvular heart disease requiring surgical intervention Preoperative congestive heart failure (New York Heart Association Function Class III or IV or ejection fraction (EF) <25% Uncontrollable asthma or chronic obstructive pulmonary disease (COPD) Greater than first degree heart block or sinus node dysfunction without a functional pacemaker Systolic blood pressure less than 90 mmHg Known hypersensitivity to adenosine Pregnancy or currently lactating Prior participation in cardiac gene and/or cardiac cell therapy

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Ronald G Crystal, MD

Organizational Affiliation

Weill Medical College of Cornell University

Official's Role

Principal Investigator

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Administration of AdVEGF-All6A+ to Myocardium of Individuals With Diffuse CAD Via Minimally Invasive Surgery

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